Monday, February 25, 2013

Accu-sane?

This is you in high school...

Hayley Chilton

Imagine you’re in high school again in the peak of puberty.
You can hardly concentrate in class with that cute boy sitting in front of you.You unconsciously spend most of the class period dreaming about how you
should just introduce yourself as his next girlfriend because, let’s face it,
you two would be perfect together! Well, that is if the unsightly blemishes on
your cheeks disappear before he has time to notice them.

No
amount of over the counter creams or medications can remedy the war zone that
is your face. Not even Windex, as promised in My Big Fat Greek Wedding. You
have a form of grade III acne vulgaris, also known as severe nodular acne. This
type of acne can be very painful and doesn’t often respond well to medications
and treatments, which can make living with it very difficult because without
treatment, the condition will progress into grade IV acne vulgaris, also known
as cystic acne. Both types III and IV are types of inflammatory acne.

So what are the physiological
differences between inflammatory and non-inflammatory acne? To put it simply non-inflammatory acne is the result of
dead cells and/or oil build-up that clog hair follicles. This type of acne is
painless and usually characterized by whether or not the follicle is open
(blackhead) or closed (whitehead).

Normal hair follicle

Blackhead

Whitehead

Meanwhile, inflammatory acne is the result of a hormone imbalance,
characterized by an elevated production of male hormones (androgens) and a
decreased production of female hormones (estrogens). The increase in androgen
production results in the escalation of sebum production, an oil produced by
the sebaceous glands under the skin near a hair follicle. Androgen production
is responsible for the elevated levels of sebum and dead skin cells shed from the
follicle. These cells clog the follicle and form a plug under which sebum
begins to accumulate. This inadvertently creates an ideal environment for the
proliferation and survival of bacteria, which leads to the painful inflammatory
lesions/pustules characteristic of individuals with this condition. Your body’s
immune system will naturally respond, sending cells to fight the infection;
however, this is rarely enough to “cure” nodular acne.

Nodular Acne

Now imagine someone told you
that you could eliminate this problem forever by taking a regimented dosage of
oral medication over the course of several months. Don’t worry there’s only a
few potential side effects which could include: nausea, muscle aches and pains,
vomiting, fever, changes in hearing and vision, weight loss, liver damage,
colon damage (this could be anything from the development of ulcers on your
colon, to rectal bleeding, bloody diarrhea, inflammation of the lining of your
colon, or the development of an autoimmune disorder in which your own body
breaks down the healthy tissue in your digestive tract), miscarriages/birth
defects if you become pregnant while on the drug, and depression/suicidal
thoughts. Would you take it? After reading this list probably not. What if I
told you the drug I just described was Accutane – a drug the millions of
Americans opted to take over the last few decades.

Before and after Accutane treatment

So what is Accutane? Accutane is an acne medication created
by Roche Pharmaceuticals. It is derivative of Vitamin A, more specifically,
isotretinoin or (13cis)-retinoic acid. Therefore, Accutane is the brand name
for a specific type of synthetic retinoid. Accutane was originally marketed as
a chemotherapy drug, when doctors noted a marked improvement in the condition
of patients’ skin. While the exact mechanism is unknown, Accutane works by
reducing oil production in the sebaceous glands underneath your skin.
Basically, the drug aims to trigger stem cells to differentiate into into new
cells in your skin that produce less oil.

So, if Accutane is a derivative of Vitamin A, does that mean
it can already be naturally found in your body? Well, not exactly…Accutane is a
synthetic retinoid engineered by Roche Pharmaceuticals. However, other
retinoids can be found naturally in your tissues and blood stream and can
also be absorbed through the digestion of foods containing Vitamin A. Normally
retinoids play roles in growth, vision, and in development – whether it’s the
development of a new baby, or the development of new neurons and new neuronal
connections in your brain. As with most chemical signals, in order for the
presence of Accutane to elicit a functional response, the right machinery in
your body needs to be present.

So let’s take a step back and make an analogy. The
brain serves as the hard-drive for your body, from which several insulated
wires (symbolic of your neurons) extend to different regions of your body.
These wires are responsible for relaying information from the hard-drive (your
brain) to different outputs (your extremities or organs). Breaking it down even
further – the hard-drive can be separated into different regions in order to
speed up the efficiency for which it processes information, just like your
brain is divided into regions dedicated to thought, motor control, eyesight,
and so forth. Given what we just outlined wouldn’t it make sense that regions
of the hard-drive with more complex circuits and wire connections would be able
to process more complex signals? What if I also told you that every time the
hard-drive was programmed to do something new it made a new wire circuit? Well
the same is true for your brain. The process of making these new neurons
(wires) and new neuron connections (new circuits formed) is called neurogenesis. There is a specific
region of the brain that we will be focusing on today called your hippocampus.

The hippocampus is the region of the brain associated with
learning and spatial memory. So, why would scientists want to look at this part
of the brain when looking at whether or not Accutane is responsible for
suicidal ideology and depression? Well, the development of new neurons and new
neuronal connections in this region of the brain is extremely important in
order for your brain to form new memories and process information. Several
studies have found that the hippocampus contains several binding proteins that
bind Accutane and regulate how your body metabolizes it.

But, how does this relate to suicidal ideology and
depression?! A study by J. Crandall demonstrated that when mice underwent
long-term elevated exposure to Accutane there was a decrease in the number of
these new neuron connections made. This in turn, made it harder for mice to
learn! Now how on earth were they able to test that? Well, mice were initially
placed in a radial arm maze and allowed to familiarize themselves/explore the
maze for a given amount of time.

Mice were then trained to find a food reward in each of the
given arms of the maze. Some mice were given a clinical dose of Accutane, the dose prescribed to Accutane patients,
prior to experimentation. The mice that weren’t given Accutane were better able
to navigate around the maze and had fewer errors when navigating than the group
of mice that did receive Accutane. Therefore, results indicate a large decrease
in the rate of spatial learning ability after Accutance treatment. Given that
several studies have found a relationship between spatial learning ability and
neurogenesis, it can be proposed that
exposure to Accutane could lead to a reduction in the formation of new neurons
and new neuronal connections.

Accutane usage has also been correlated with the onset of
suicidal thoughts, anger and depression in several patients. While it has been
proposed that a decrease in neurogenesis can be accompanied by depression,
another study by K.C. O’Reilly showed that chronically administering Accutane
to mice could also contribute to this behavior. Mice were again given a
clinical dose of Accutane and their levels of mobility were assessed. Those
that were given Accutane showed decreased levels of mobility, a behavior
characteristic to an individual with depression. I’m sure anyone who has
experienced depression or knows someone who has depression can relate to this
concept – being depressed literally makes you want to do nothing. Accutane could thus have an influence on dopamine levels. So, how does
dopamine relate to depression?

Well, dopamine is a hormone released in your brain that
is associated with your brain’s “reward” system. “Rewards” increase the level
of dopamine release in your brain, which leads to positive, happy, and or
satisfactory feelings. Highly addictive drugs are often responsible for
eliciting this response, which is why people have a hard time quitting
addictive habits…because it literally feels so good! Therefore, while the
direct mechanism is unknown, scientists have hypothesized that Accutane could
be involved in inhibiting dopamine release. Another supportive study by Y.
Sakai also perpetuates the notion that if Accutane results in a decrease in the
amount of neurons formed/retained in mice, through the disruption of the normal
retinoid-signaling pathway, Accutane usage may somehow be linked to depression
in humans.

In 2009,
Accutane was recalled from the market due to several lawsuits filed against it,
with respect to birth defects, suicide, and inflammatory bowel disease. While
there are several generic isotretinoin drugs available, the side effects that
they cause should be taken into heavy consideration before you decide whether
or not you’re willing to compromise other bodily functions for clear skin. Here
we merely touched on how Accutane affects the brain, but as mentioned, there
are several other ways that this drug attacks more than just acne in your body.

NOTE: In the experiments scientists used 13-ci-retinoic
acid, not the brand name Accutane. However, for the sake of simplicity and
conceptual understanding it was referred to as Accutane throughout this blog.

3 comments:

Very interesting Hayley! I had no idea that the side-effects of this acne treatment were that extensive! It's amazing that with all those side-effects a drug like Accutane could even make it to the market to begin with! Just shows that where there are customers willing to pay, pharmaceutical companies will find a way!

Great topic Hayley! I'm curious as to why Accutane was recalled in 2009 but none of the other drugs were. If these side effects are such a concern, why is this drug still on the market? I can't imagine that if the FDA had sufficient evidence, they wouldn't hesitate to ban isotretinoin across the board. Food for thought!

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